tbuckley/cabot-search huggingface dataset:
Addressing the diagnostic gap in hypertension through possible interventions and scale-up: A microsimulation study
Authors: Lisa Koeppel, Sabine Dittrich, Sergio Brenner Miguel, Sergio Carmona, Stefano Ongarello, Beatrice Vetter, Jennifer Elizabeth Cohn, Till Baernighausen, Pascal Geldsetzer, Claudia M. Denkinger
Journal: PLoS Medicine (2022)

Background Cardiovascular diseases (CVDs) are the leading cause of mortality globally with almost a third of all annual deaths worldwide. Low- and middle-income countries (LMICs) are disproportionately highly affected covering 80% of these deaths. For CVD, hypertension (HTN) is the leading modifiable risk factor. The comparative impact of diagnostic interventions that improve either the accuracy, the reach, or the completion of HTN screening in comparison to the current standard of care has not been estimated. Methods and findings This microsimulation study estimated the impact on HTN-induced morbidity and mortality in LMICs for four different scenarios: (S1) lower HTN diagnostic accuracy; (S2) improved HTN diagnostic accuracy; (S3) better implementation strategies to reach more persons with existing tools; and, lastly, (S4) the wider use of easy-to-use tools, such as validated, automated digital blood pressure measurement devices to enhance screening completion, in comparison to the current standard of care (S0). Our hypothetical population was parametrized using nationally representative, individual-level HPACC data and the global burden of disease data. The prevalence of HTN in the population was 31% out of which 60% remained undiagnosed. We investigated how the alteration of a yearly blood pressure screening event impacts morbidity and mortality in the population over a period of 10 years. The study showed that while improving test accuracy avoids 0.6% of HTN-induced deaths over 10 years (13,856,507 [9,382,742; 17,395,833]), almost 40 million (39,650,363 [31,34,233, 49,298,921], i.e., 12.7% [9.9, 15.8]) of the HTN-induced deaths could be prevented by increasing coverage and completion of a screening event in the same time frame. Doubling the coverage only would still prevent 3,304,212 million ([2,274,664; 4,164,180], 12.1% [8.3, 15.2]) CVD events 10 years after the rollout of the program. Our study is limited by the scarce data available on HTN and CVD from LMICs. We had to pool some parameters across stratification groups, and additional information, such as dietary habits, lifestyle choice, or the blood pressure evolution, could not be considered. Nevertheless, the microsimulation enabled us to include substantial heterogeneity and stochasticity toward the different income groups and personal CVD risk scores in the model. Conclusions While it is important to consider investing in newer diagnostics for blood pressure testing to continuously improve ease of use and accuracy, more emphasis should be placed on screening completion.
Biomaterial mediated simultaneous delivery of spermine and alpha ketoglutarate modulate metabolism and innate immune cell phenotype in sepsis mouse models
Authors: Sahil Inamdar, Tina Tylek, Abhirami Thumsi, Abhirami P. Suresh, Madhan Mohan Chandra Sekhar Jaggarapu, Michelle Halim, Shivani Mantri, Arezoo Esrafili, Nathan D. Ng, Elizabeth Schmitzer, Kelly Lintecum, Camila de Ávila, John D. Fryer, Ying Xu, Kara L. Spiller, Abhinav P. Acharya
Journal: Biomaterials (2022)
Project Harmony: A Meta-Analysis With Individual Patient Data on Behavioral and Pharmacologic Trials for Comorbid Posttraumatic Stress and Alcohol or Other Drug Use Disorders
Authors: Denise A. Hien, Antonio A. Morgan-López, Lissette M. Saavedra, Lesia M. Ruglass, Ai Ye, Teresa López-Castro, Skye Fitzpatrick, Therese K. Killeen, Sonya B. Norman, Chantel T. Ebrahimi, Sudie E. Back
Journal: American Journal of Psychiatry (2022)

Treatment efficacy for co-occurring posttraumatic stress disorder (PTSD) and substance use disorders is well established, yet direct evidence for comparative effectiveness across treatments is lacking. The present study compared the effectiveness of several behavioral and pharmacological therapies for adults with co-occurring PTSD and alcohol or other drug use disorders.
Resting-State Connectivity and Response to Psychotherapy Treatment in Adolescents and Adults With OCD: A Randomized Clinical Trial
Authors: Stefanie Russman Block, Luke J. Norman, Xiaoxi Zhang, Kristin A. Mannella, Huan Yang, Mike Angstadt, James L. Abelson, Joseph A. Himle, Stephan F. Taylor, Kate D. Fitzgerald
Journal: American Journal of Psychiatry (2022)

Cortical-subcortical hyperconnectivity related to affective-behavioral integration and cortical network hypoconnectivity related to cognitive control have been demonstrated in obsessive-compulsive disorder (OCD); the study objective was to examine whether these connectivity patterns predict treatment response.
In Search of Biomarkers to Guide Interventions in Autism Spectrum Disorder: A Systematic Review
Authors: Mara Parellada, Álvaro Andreu-Bernabeu, Mónica Burdeus, Antonia San José Cáceres, Elena Urbiola, Linda L. Carpenter, Nina V. Kraguljac, William M. McDonald, Charles B. Nemeroff, Carolyn I. Rodriguez, Alik S. Widge, Matthew W. State, Stephan J. Sanders
Journal: American Journal of Psychiatry (2022)

The aim of this study was to catalog and evaluate response biomarkers correlated with autism spectrum disorder (ASD) symptoms to improve clinical trials.A systematic review of MEDLINE, Embase, and Scopus was conducted in April 2020. Seven criteria were applied to focus on original research that includes quantifiable response biomarkers measured alongside ASD symptoms. Interventional studies or human studies that assessed the correlation between biomarkers and ASD-related behavioral measures were included.A total of 5,799 independent records yielded 280 articles for review that reported on 940 biomarkers, 755 of which were unique to a single publication. Molecular biomarkers were the most frequently assayed, including cytokines, growth factors, measures of oxidative stress, neurotransmitters, and hormones, followed by neurophysiology (e.g., EEG and eye tracking), neuroimaging (e.g., functional MRI), and other physiological measures. Studies were highly heterogeneous, including in phenotypes, demographic characteristics, tissues assayed, and methods for biomarker detection. With a median total sample size of 64, almost all of the reviewed studies were only powered to identify biomarkers with large effect sizes. Reporting of individual-level values and summary statistics was inconsistent, hampering mega- and meta-analysis. Biomarkers assayed in multiple studies yielded mostly inconsistent results, revealing a "replication crisis."There is currently no response biomarker with sufficient evidence to inform ASD clinical trials. This review highlights methodological imperatives for ASD biomarker research necessary to make definitive progress: consistent experimental design, correction for multiple comparisons, formal replication, sharing of sample-level data, and preregistration of study designs. Systematic "big data" analyses of multiple potential biomarkers could accelerate discovery.
U.S. Health Insurance Coverage and Financing
Authors: Sabrina Corlette, Christine H. Monahan
Journal: New England Journal of Medicine (2022)

Interview with Prof. Sabrina Corlette on the history of the U.S. health insurance system and persistent coverage and affordability challenges. (09:34)Download The United States has a patchwork system of health insurance coverage, in which people's access to coverage and services varies with their birthplace, age, job, income, location, and health status.
Reducing harm from overuse of healthcare
Authors: Karen Born, Wendy Levinson, Loren de Freitas
Journal: BMJ (2022)

Reducing overuse and waste in healthcare has been identified as an essential part of providing high quality care for health systems globally. 1Unnecessary tests, treatments, and procedures can have serious implications for individual patients, healthcare systems, and the planet.Individuals can be directly harmed through, for example, diagnostic and testing cascades that can cause side effects and lead to substantial anxiety for patients, caregivers, and families.Unnecessary medication can lead to drug interactions, and overprescribing is a driver of public health crises such as antimicrobial resistance 2 and the prescription opioid abuse epidemic.
Epigenetic modulation of neuroblastoma enhances T cell and NK cell immunogenicity by inducing a tumor-cell lineage switch
Authors: Annelisa M Cornel, Ester Dunnebach, Damon A Hofman, Sanjukta Das, Satyaki Sengupta, Femke van den Ham, Judith Wienke, Josephine G M Strijker, Denise A M H van den Beemt, Anke H W Essing, Bianca Koopmans, Sem A G Engels, Vania Lo Presti, Celina S Szanto, Rani E George, Jan J Molenaar, Sebastiaan van Heesch, Miranda P Dierselhuis, S Nierkens
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Immunotherapy in high-risk neuroblastoma (HR-NBL) does not live up to its full potential due to inadequate (adaptive) immune engagement caused by the extensive immunomodulatory capacity of HR-NBL. We aimed to tackle one of the most notable immunomodulatory processes in neuroblastoma (NBL), absence of major histocompatibility complex class I (MHC-I) surface expression, a process greatly limiting cytotoxic T cell engagement. We and others have previously shown that MHC-I expression can be induced by cytokine-driven immune modulation. Here, we aimed to identify tolerable pharmacological repurposing strategies to upregulate MHC-I expression and therewith enhance T cell immunogenicity in NBL. Methods Drug repurposing libraries were screened to identify compounds enhancing MHC-I surface expression in NBL cells using high-throughput flow cytometry analyses optimized for adherent cells. The effect of positive hits was confirmed in a panel of NBL cell lines and patient-derived organoids. Compound-treated NBL cell lines and organoids were cocultured with preferentially expressed antigen of melanoma (PRAME)-reactive tumor-specific T cells and healthy-donor natural killer (NK) cells to determine the in vitro effect on T cell and NK cell cytotoxicity. Additional immunomodulatory effects of histone deacetylase inhibitors (HDACi) were identified by transcriptome and translatome analysis of treated organoids. Results Drug library screening revealed MHC-I upregulation by inhibitor of apoptosis inhibitor (IAPi)- and HDACi drug classes. The effect of IAPi was limited due to repression of nuclear factor kappa B (NFκB) pathway activity in NBL, while the MHC-I-modulating effect of HDACi was widely translatable to a panel of NBL cell lines and patient-derived organoids. Pretreatment of NBL cells with the HDACi entinostat enhanced the cytotoxic capacity of tumor-specific T cells against NBL in vitro, which coincided with increased expression of additional players regulating T cell cytotoxicity (eg, TAP1/2 and immunoproteasome subunits). Moreover, MICA and MICB, important in NK cell cytotoxicity, were also increased by entinostat exposure. Intriguingly, this increase in immunogenicity was accompanied by a shift toward a more mesenchymal NBL cell lineage. Conclusions This study indicates the potential of combining (immuno)therapy with HDACi to enhance both T cell-driven and NKcell-driven immune responses in patients with HR-NBL.
Preconditioning of the immune system modulates the response of papillary thyroid cancer to immune checkpoint inhibitors
Authors: Fabiana Pani, Yoshinori Yasuda, Sylvie T Rousseau, Kevin C Bermea, Solmaz Roshanmehr, Rulin Wang, Srinivasan Yegnasubramanian, Patrizio Caturegli, Luigi Adamo
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background The response of solid tumors such as papillary thyroid cancer (PTC) to immune checkpoint inhibitors (ICIs) is highly variable. The biological basis of this variability remains unknown. Methods To test the hypothesis that preconditioning of the immune system modulates the therapeutic effect of ICIs, we used a murine model where PTC and iodine exacerbated thyroiditis (IET) can be induced in a temporally predictable fashion. A total of 122 mice were divided into 3 experimental groups. In the first one, named concomitant IET and PTC (No.=40), IET, and PTC were induced at the same time; in the second one, named pre-existing IET (No.=44), IET was induced prior to the induction of PTC; in the third one, named no IET (No.=38), only PTC was induced. Following disease induction, mice of each group were treated with anti-PD-1 antibody, anti-lymphocyte activation gene 3 antibody (anti-Lag3), anti-T-cell immunoglobulin and mucin domain 3 antibody (anti-Tim3), or IgG control. Ten weeks after the initial ICI injection, mice were sacrificed to collect the thyroid gland for histological analysis, to quantify the incidence and burden of PTC, and to perform high-throughput single-cell RNA sequencing of infiltrating CD45 + cells. Results In the concomitant IET and PTC group, ICI treatment reduced PTC incidence (p=0.002 comparing treatment with any ICI vs control), while it had no effect in the pre-existing IET and no IET groups. Single-cell sequencing of thyroidal CD45 + cells showed that the different ICIs tested had both specific and shared effects on all the components of the thyroidal immune cell infiltrate. The shared effect of the tested ICIs was dependent on the presence of pre-existing versus concomitant IET. In the context of concomitant IET, ICI treatment resulted in the modulation of a greater number of pathways related to both innate and adaptive immunity. Conclusions Response to ICIs depends on the status of the immune system of the treated individual. Modulation of the immune system should be explored as a tool to improve response to ICIs in patients with PTC or other forms of cancer.
How decreasing T cell signaling unexpectedly results in autoimmunity
Authors: Jaeu Yi, Chyi-Song Hsieh
Journal: The Journal of Experimental Medicine (2022)

In this issue of JEM, Tanaka et al. (2022. J. Exp. Med.https://doi.org/10.1084/jem.20220386) advance our understanding of how genetic mutants that decrease T cell recognition of antigen, a critical event for immune activation to invading microbes and virus, paradoxically results in autoimmunity.
Repurposing a tricyclic antidepressant in tumor and metabolism disease treatment through fatty acid uptake inhibition
Authors: Qiaoyun Chu, Jing An, Ping Liu, Yihan Song, Xuewei Zhai, Ronghui Yang, Jing Niu, Chuanzhen Yang, Binghui Li
Journal: The Journal of Experimental Medicine (2022)

Fatty acid uptake is essential for cell physiological function, but detailed mechanisms remain unclear. Here, we generated an acetyl-CoA carboxylases (ACC1/2) double-knockout cell line, which lacked fatty acid biosynthesis and survived on serum fatty acids and was used to screen for fatty acid uptake inhibitors. We identified a Food and Drug Administration–approved tricyclic antidepressant, nortriptyline, that potently blocked fatty acid uptake both in vitro and in vivo. We also characterized underlying mechanisms whereby nortriptyline provoked lysosomes to release protons and induce cell acidification to suppress macropinocytosis, which accounted for fatty acid endocytosis. Furthermore, nortriptyline alone or in combination with ND-646, a selective ACC1/2 inhibitor, significantly repressed tumor growth, lipogenesis, and hepatic steatosis in mice. Therefore, we show that cells actively take up fatty acids through macropinocytosis, and we provide a potential strategy suppressing tumor growth, lipogenesis, and hepatic steatosis through controlling the cellular level of fatty acids.
Human genetic diversity alters off-target outcomes of therapeutic gene editing
Authors: Samuele Cancellieri, Jing Zeng, Linda Yingqi Lin, Manuel Tognon, My Anh Nguyen, Jiecong Lin, Nicola Bombieri, Stacy A. Maitland, Marioara-Felicia Ciuculescu, Varun Katta, Shengdar Q. Tsai, Myriam Armant, Scot A. Wolfe, Rosalba Giugno, Daniel E. Bauer, Luca Pinello
Journal: Nature Genetics (2022)
Targeting the bicarbonate transporter SLC4A4 overcomes immunosuppression and immunotherapy resistance in pancreatic cancer
Authors: Federica Cappellesso, Marie-Pauline Orban, Niranjan Shirgaonkar, Emanuele Berardi, Jens Serneels, Marie-Aline Neveu, Daria Di Molfetta, Francesca Piccapane, Rosa Caroppo, Lucantonio Debellis, Tessa Ostyn, Nicolas Joudiou, Lionel Mignion, Elena Richiardone, Bénédicte F. Jordan, Bernard Gallez, Cyril Corbet, Tania Roskams, Ramanuj DasGupta, Sabine Tejpar, Mario Di Matteo, Daniela Taverna, Stephan J. Reshkin, Baki Topal, Federico Virga, Massimiliano Mazzone
Journal: Nature Cancer (2022)

Solid tumors are generally characterized by an acidic tumor microenvironment (TME) that favors cancer progression, therapy resistance and immune evasion. By single-cell RNA-sequencing analysis in individuals with pancreatic ductal adenocarcinoma (PDAC), we reveal solute carrier family 4 member 4 (SLC4A4) as the most abundant bicarbonate transporter, predominantly expressed by epithelial ductal cells. Functionally, SLC4A4 inhibition in PDAC cancer cells mitigates the acidosis of the TME due to bicarbonate accumulation in the extracellular space and a decrease in lactate production by cancer cells as the result of reduced glycolysis. In PDAC-bearing mice, genetic or pharmacological SLC4A4 targeting improves T cell-mediated immune response and breaches macrophage-mediated immunosuppression, thus inhibiting tumor growth and metastases. In addition, Slc4a4 targeting in combination with immune checkpoint blockade is able to overcome immunotherapy resistance and prolong survival. Overall, our data propose SLC4A4 as a therapeutic target to unleash an antitumor immune response in PDAC.
Safety and immunogenicity of a bivalent SARS-CoV-2 protein booster vaccine, SCTV01C in adults previously vaccinated with inactivated vaccine: A randomized, double-blind, placebo-controlled phase 1/2 clinical trial
Authors: Suad Hannawi, Linda Saf Eldin, Alaa Abuquta, Ahmad Alamadi, Sally A. Mahmoud, Jian Li, Yuanxin Chen, Liangzhi Xie
Journal: Journal of Infection (2022)
γδIL17 under control
Authors: Guillem Sanchez Sanchez, David Vermijlen
Journal: The Journal of Experimental Medicine (2022)

In the mouse, γδ IL17 cells are poised to make IL-17, and these cells have been involved in various infection and cancer models. Edwards et al. (2022. J. Exp. Med.https://doi.org/10.1084/jem.20211431) now report how different γδIL17 subsets are controlled during homeostasis and cancer.
Smart dental materials for antimicrobial applications
Authors: Carolina Montoya, Lina Roldan, Michelle Yu, Sara Valliani, Christina Ta, Maobin Yang, Santiago Orrego
Journal: Bioactive Materials (2022)

Smart biomaterials can sense and react to physiological or external environmental stimuli (e.g., mechanical, chemical, electrical, or magnetic signals). The last decades have seen exponential growth in the use and development of smart dental biomaterials for antimicrobial applications in dentistry. These biomaterial systems offer improved efficacy and controllable bio-functionalities to prevent infections and extend the longevity of dental devices. This review article presents the current state-of-the-art of design, evaluation, advantages, and limitations of bioactive and stimuli-responsive and autonomous dental materials for antimicrobial applications. First, the importance and classification of smart biomaterials are discussed. Second, the categories of bioresponsive antibacterial dental materials are systematically itemized based on different stimuli, including pH, enzymes, light, magnetic field, and vibrations. For each category, their antimicrobial mechanism, applications, and examples are discussed. Finally, we examined the limitations and obstacles required to develop clinically relevant applications of these appealing technologies.
KMT2D deficiency drives lung squamous cell carcinoma and hypersensitivity to RTK-RAS inhibition
Authors: Yuanwang Pan, Han Han, Hai Hu, Hua Wang, Yueqiang Song, Yuan Hao, Xinyuan Tong, Ayushi S. Patel, Selim Misirlioglu, Sittinon Tang, Hsin-Yi Huang, Ke Geng, Ting Chen, Angeliki Karatza, Fiona Sherman, Kristen E. Labbe, Fan Yang, Alison Chafitz, Chengwei Peng, Chenchen Guo, Andre L. Moreira, Vamsidhar Velcheti, Sally C.M. Lau, Pengfei Sui, Haiquan Chen, J. Alan Diehl, Anil K. Rustgi, Adam J. Bass, John T. Poirier, Xiaoyang Zhang, Hongbin Ji, Hua Zhang, Kwok-Kin Wong
Journal: Cancer Cell (2022)

Lung squamous cell carcinoma (LUSC) represents a major subtype of lung cancer with limited treatment options. KMT2D is one of the most frequently mutated genes in LUSC (>20%), and yet its role in LUSC oncogenesis remains unknown. Here, we identify KMT2D as a key regulator of LUSC tumorigenesis wherein Kmt2d deletion transforms lung basal cell organoids to LUSC. Kmt2d loss increases activation of receptor tyrosine kinases (RTKs), EGFR and ERBB2, partly through reprogramming the chromatin landscape to repress the expression of protein tyrosine phosphatases. These events provoke a robust elevation in the oncogenic RTK-RAS signaling. Combining SHP2 inhibitor SHP099 and pan-ERBB inhibitor afatinib inhibits lung tumor growth in Kmt2d-deficient LUSC murine models and in patient-derived xenografts (PDXs) harboring KMT2D mutations. Our study identifies KMT2D as a pivotal epigenetic modulator for LUSC oncogenesis and suggests that KMT2D loss renders LUSC therapeutically vulnerable to RTK-RAS inhibition.
Development and systematic characterization of GelMA/alginate/PEGDMA/xanthan gum hydrogel bioink system for extrusion bioprinting
Authors: Jiannan Li, Seyedsina Moeinzadeh, Carolyn Kim, Chi-Chun Pan, George Weale, Sungwoo Kim, Geoffrey Abrams, Aaron W. James, HyeRan Choo, Charles Chan, Yunzhi Peter Yang
Journal: Biomaterials (2022)
Corrigendum to “Pembrolizumab plus Olaparib in Patients with Metastatic Castration-resistant Prostate Cancer: Long-term Results from the Phase 1b/2 KEYNOTE-365 Cohort A Study” [Eur Urol 83 (2023) 15–26]
Authors: Evan Y. Yu, Josep M. Piulats, Gwenaelle Gravis, Peter C.C. Fong, Tilman Todenhöfer, Brigitte Laguerre, Jose A. Arranz, Stephane Oudard, Christophe Massard, Julia Heinzelbecker, Luke T. Nordquist, Joan Carles, Michael P. Kolinsky, Marinela Augustin, Howard Gurney, Ali Tafreshi, Xin Tong Li, Ping Qiu, Christian H. Poehlein, Charles Schloss, Johann S. de Bono
Journal: European Urology (2022)
Recurrent rectal bleeding in a teenager caused by a cavernous haemangioma of the sigmoid colon
Authors: Marta Martín González, Álvaro Pineda Torcuato, Maria Luisa Martin Jimenez, Isabel Alonso Sebastián, Jose Luis Martinez Porras, Gala Silvestre Egea, Concepción Gonzalez Hernando
Journal: The Lancet (2022)
FAM3A maintains metabolic homeostasis by interacting with F1-ATP synthase to regulate the activity and assembly of ATP synthase
Authors: Han Yan, Yuhong Meng, Xin Li, Rui Xiang, Song Hou, Junpei Wang, Lin Wang, Xiaoxing Yu, Ming Xu, Yujing Chi, Jichun Yang
Journal: Metabolism (2022)
Discovery of a potent allosteric activator of DGKQ that ameliorates obesity-induced insulin resistance via the sn-1,2-DAG-PKCε signaling axis
Authors: Zu-Guo Zheng, Yin-Yue Xu, Wen-Ping Liu, Yang Zhang, Chong Zhang, Han-Ling Liu, Xiao-Yu Zhang, Run-Zhou Liu, Yi-Ping Zhang, Meng-Ying Shi, Hua Yang, Ping Li
Journal: Cell Metabolism (2022)
Efficient in vivo neuronal genome editing in the mouse brain using nanocapsules containing CRISPR-Cas9 ribonucleoproteins
Authors: Jeanette M. Metzger, Yuyuan Wang, Samuel S. Neuman, Kathy J. Snow, Stephen A. Murray, Cathleen M. Lutz, Viktoriya Bondarenko, Jesi Felton, Kirstan Gimse, Ruosen Xie, Dongdong Li, Yi Zhao, Matthew T. Flowers, Heather A. Simmons, Subhojit Roy, Krishanu Saha, Jon E. Levine, Marina E. Emborg, Shaoqin Gong
Journal: Biomaterials (2022)
Highlights 2022: sharpening the focus on powerful health stories
Authors: Joanna Palmer, Danilo Buonsenso, Paresh Kumar, Aftab Nohri, Sonia Hegde, Al Ogawa, Pearl Gan, Nicolas Beaumont, Rajiv Kumar Solanki, Sindhuja Khajuria, Chandrakant Lahariya, Sanjib Kumar Sharma, Srista Manandhar, Samantha Kumara Senavirathna, K V Balasubramanya, Sumitra Acharya, Hugo Rolando Gonzalez Cárdenas, Arpan Basuchowdhury, Saverio Bellizzi, Alexander Kumar
Journal: The Lancet (2022)